Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil.
J Appl Toxicol. 2013 Jun;33(6):480-7. doi: 10.1002/jat.1777. Epub 2011 Dec 19.
Organoselenium compounds have important pharmacological properties. However, these compounds can cause toxicity, typically related to oxidation of endogenous thiols. The aim of this study was to investigate whether 2,2'-dithienyl diselenide (DTDS) has potential toxicity in vitro and in vivo. Therefore, sulfhydryl-containing enzyme activities, δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na(+) -K(+) -ATPase were used to predict DTDS toxicity in rat brain homogenate in vitro. In in vivo experiments, a DTDS administration (50 or 100 mg kg(-1) , p.o.) to rats was performed and toxicological parameters were determined. DTDS inhibited δ-ALA-D (IC50 2 µm) and Na(+) -K(+) -ATPase (IC50 17 µm) activities in vitro. The inhibitory effect of DTDS on δ-ALA-D and Na(+) -K(+) -ATPase activities was restored by dithiothreitol. DTDS (5-25 µm) elicited a thiol oxidase-like activity. In vivo, DTDS (50 and 100 mg kg(-1) ) caused systemic toxicity, evidenced by a decrease in water and food intakes and body weight gain, as well as the death of rats. DTDS at the dose of 100 mg kg(-1) increased plasma alanine and aspartate aminotransferase activities and decreased urea levels. At 50 and 100 mg kg(-1) , it increased lipid peroxidation levels. At the highest dose, DTDS inhibited δ-ALA-D activity. By contrast, Na(+) -K(+) -ATPase activity and antioxidant defense were not altered in the brains of rats exposed to DTDS. In conclusion, interaction with the cisteinyl residues seems to mediate the inhibitory effect of DTDS on sulfhydryl-containing enzymes in vitro. In addition, high oral doses of DTDS induce toxicity in rats.
有机硒化合物具有重要的药理学性质。然而，这些化合物可能会引起毒性，通常与内源性巯基的氧化有关。本研究旨在探讨 2,2'-二噻吩基二硒醚（DTDS）在体外和体内是否具有潜在毒性。因此，使用含巯基的酶活性、δ-氨基酮戊酸脱水酶（δ-ALA-D）和 Na(+) -K(+) -ATPase 来预测 DTDS 在大鼠脑匀浆中的体外毒性。在体内实验中，给予大鼠 DTDS （50 或 100mg/kg，po），并测定毒理学参数。DTDS 在体外抑制 δ-ALA-D（IC50 为 2µm）和 Na(+) -K(+) -ATPase（IC50 为 17µm）活性。DTDS 对 δ-ALA-D 和 Na(+) -K(+) -ATPase 活性的抑制作用可被二硫苏糖醇恢复。DTDS（5-25µm）诱导一种类似硫氧还蛋白氧化酶的活性。在体内，DTDS（50 和 100mg/kg）引起全身毒性，表现为水和食物摄入量减少、体重增加以及大鼠死亡。DTDS 剂量为 100mg/kg 时，可使血浆丙氨酸和天冬氨酸氨基转移酶活性升高，尿素水平降低。在 50 和 100mg/kg 时，可增加脂质过氧化水平。在最高剂量时，DTDS 抑制 δ-ALA-D 活性。相反，暴露于 DTDS 的大鼠大脑中的 Na(+) -K(+) -ATPase 活性和抗氧化防御系统未发生改变。综上所述，与半胱氨酸残基的相互作用似乎介导了 DTDS 对体外含巯基酶的抑制作用。此外，高口服剂量的 DTDS 可引起大鼠毒性。
